The human placenta normally serves as a barrier to direct transmission of viruses from the maternal circulation to the fetus. This is confirmed by the fact that approximately 25% of the infected babies of untreated mothers positive for the HIV virus are infected in utero. What determines the apparent differential transmission in different pregnancies is unknown. It has been suggested that the placenta's protective role may be compromised by maternal exposure to ethanol. While no data are available to suggest how this might occur, there are two obvious hypotheses. First, chronic exposure to ethanol might injure the placenta, producing a long-term malfunction. Second, acute exposure might result in a temporary failure of protective function. We propose to test both hypotheses in a human placental perfusion system. Passage of the HIV virus from the maternal circulation to the fetal circulation will be quantified over an 18 hour perfusion in placentae of mothers who report three or more alcoholic drinks per day versus those who report no exposure to ethanol. If ethanol-exposed placentae permit more virus to cross to the fetal circulation than unexposed placentae, chronic maternal ethanol exposure will be implicated as a factor in passage of the HIV virus. In half the placentae from each maternal group, ethanol will be added directly to the perfusion medium. If perfusions with ethanol exhibit increased passage of virus, acute exposure will be implicated as playing a role in transmission. Because there is evidence that transmission occurs only when the placenta itself is infected, the same chronic and acute exposure conditions will be studied in placentae experimentally infected with HIV-1 and monitored in human placental explant cultures. These experiments will provide tests of a third important hypothesis: that ethanol exposure increases the risk of transmission by increasing the degree of infection in the placenta. The experiments proposed will provide the first evidence on whether ethanol plays a role in direct transmission of the HIV virus to the fetus.